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E. A. Sims et al. / Tetrahedron Letters 52 (2011) 1871–1873
Table 1
due to the nature of cyclizing larger rings: significant oligomeriza-
tion/polymerization likely occured, as evidenced by the formation
of a non-volatile, colored byproduct and reduced product recovery,
even with high dilution and slow addition of diester. Thus, we
sought to develop a mild, high-yielding synthesis of 1,3-cyclooc-
tanedione starting from an inexpensive, readily-available
substrate.
Initially, we were inspired by a kg-scale preparation of 1,3-
cycloheptanedione,20,21 whose key step relies on the cycloaddition
between dichloroacetyl chloride and 1-trimethylsilyloxycyclopen-
tene. We hypothesized that this synthetic approach could be easily
adapted to prepare 1,3-cyclooctanedione. However, we abandoned
this route after experiencing difficulty obtaining significant cou-
pling between 1-trimethylsilyloxycyclohexene and dichloroacetyl
chloride. Ultimately, cyclooctanone was chosen as a starting point
as it is inexpensive ($77 per 100 g via Aldrich), readily available,
and several potential methods for installing the ketone functional-
ity at the b-position were identified, including epoxidation and
subsequent Pd-catalyzed rearrangement22,23 as well as the direct
Wacker–Tsuji oxidation24 (Scheme 2).
Isolated yields of dione (6) via the Wacker–Tsuji oxidation of enone (5) for a variety of
catalyst and reactant amounts, as well as temperature
Na2PdCl4
(mol equiv)
tert-BuOOH
(mol equiv)
Temperature
(°C)
Yield
(%)
0.2
0.2
0.2
0.2
0.1
0.1
0.4
1.5
1.5
3
3
1.5
3
50
100
50
30
50
24
11
36
36
30
37
22
50
50
1.5
sonable purity. Quantitative dehydrobromination of crude ketal
bromide 3 was accomplished after reacting for 1 h in neat 1,8-diaz-
abicycloundec-7-ene (DBU) at 160 °C. We note that the direct con-
version of cyclooctanone 1 to the bromo ketal 3 has been reported
elsewhere.29,30 Crude product 4 was deprotected via trans-ketaliza-
tion in PPTS/acetone/water, and resultant enone 5 was recovered
in high yield after purification by flash chromatography. Note that
while Plumet23 reports a method to synthesize enone 5 in two
steps from cyclooctanedione, we feel the extra two steps for the
present scheme are justified: The overall yield is higher (78% vs
49%), both require just one chromatographic purification (for the
final enone), and the palladium reagent used in the Plumet method
From the starting cyclooctanone (1), enone 5 was synthesized in
four steps and 78% yield via
a-bromination followed by elimina-
tion, an established method to introduce an
a,b C@C double
bond.25 Bromination of ketone (1) was accomplished in excellent
yield (90%, Scheme 3) with 1.5 equiv of Br2 in ethanolic hydrochlo-
ric acid and the product was pure enough after standard aqueous
workup to obviate chromatographic purification.
(73 mol %) would add considerable cost to
preparation.
a large scale
Many attempts to effect direct dehydrobromination on 2 with
various bases and solvent systems were made (KOH in isopropanol,
DBU in toluene or dichloromethane,26 and LiBr/Li2CO3 in DMF27).
All such attempts, however, failed to generate significant quantity
of enone 5. Thus, a two-step protection/deprotection of the ketone
moiety was adopted.28 Formation of bromo ketal 3 under Dean–
Stark conditions was achieved in near-quantitative yield and rea-
Two potential methods to convert enone 5 to 1,3-cyclooctanedi-
one (6) were identified involving epoxidation then palladium-cat-
alyzed rearrangement.31,23 However, after an initial attempt to
form the epoxide from enone (5) under Weitz–Scheffer conditions
(aq H2O2 or TBHP and cat. NaOH)32 failed, we found that Wacker–
Tsuji oxidation conditions gave the desired dione in a single step
(Scheme 3).24 After briefly screening reaction conditions (Table 1),
conversion of enone 5 to dione 6 was realized in 37% yield by treat-
ment with 0.1 equiv Na2PdCl4 and 3 equiv tert-BuOOH in AcOH/
H2O (1:1) at 50 °C—undesired formation of unidentified side prod-
ucts resulted in the modest yield of this step. Given the high yields
and simple purifications for the preceding steps, even with a yield
<40% for the final step, this represents a significant improvement
over the standard method for 1,3-cyclooctanedione preparation
(Scheme 1).17 Furthermore, to the best of our knowledge, no suc-
cessful application of the Wacker–Tsuji application to a cyclic sub-
strate has ever been reported.
In summary, we have described a new method to synthesize
1,3-cyclooctanedione in five steps (Scheme 3) using an inexpensive
starting material, robust reactions, and with only two steps requir-
ing chromatographic purification. In addition, the first successful
application of the Wacker oxidation in the direct synthesis of a cyc-
lic 1,3-dione is shown. Using this method, we were able to gener-
ate 15+ g of dione 6 in 29% overall yield which can be used to
further synthesize DIFO3 for SPAAC.
Scheme 2. Strategy for synthesis of 1,3-cyclooctanedione.
Acknowledgments
The authors would like to thank C. Bertozzi and J. Baskin for ini-
tial communication concerning these efforts. This work was funded
by the Howard Hughes Medical Institute. Fellowship assistance to
C.A.D. was awarded by the US Department of Education’s Graduate
Assistantships in Areas of National Need program.
Supplementary data
Scheme 3. Complete synthesis of 1,3-cyclooctanedione (6) from cyclooctanone (1)
with reaction conditions and obtained yields. Full reaction conditions, as well as 1H,
13C, and COSY NMR and HR-MAS characterization for all compounds can be found in
the Supplementary data.
Supplementary data associated with this article can be found, in